An. Bras. Dermatol. vol.84 no.6 Rio de Janeiro nov./dez. 2009

http://dx.doi.org/10.1590/S0365-05962009000600008

IPhD in Pathology, Dermatologist of the
Department of Dermatology and Radiation Therapy of Botucatu School of Medicine
(Unesp) - Botucatu (SP), BrazilIIPhD Assistant Professor of the Department
of Dermatology and Radiation Therapy of Botucatu School of Medicine (Unesp) -
Botucatu (SP), BrazilIIIPhD Assistant Professor of the Department
of Pathology of Botucatu School of Medicine (Unesp) - Botucatu (SP), BrazilIVAdjunct Professor of the Department
of Pathology of Botucatu School of Medicine (Unesp) - Botucatu (SP), Brazil

Melasma is a common dermatosis that involves changes in normal skin pigmentation,
resulting from the hyperactivity of epidermal melanocytes. The consequent hyperpigmentation
is mostly induced by ultraviolet radiation. Clinically, melasma is characterized
by light to dark brown macules that usually occur on the face, although they
can also affect the cervical and anterior thoracic regions and upper members.Fertile
age women and those with intermediate skin phototypes are most likely to develop
melasma. Most of its physiopathogenics is not yet fully understood, but there
is a relation with genetic and hormonal factors, drugs and cosmetics use, endocrinopathies
and sun exposure. The authors discuss the main aspects associated with skin
pigmentation and the development of melasma.

The skin is the most visible aspect of the human
phenotype and its color is one of its most variable features. Little is known about
the genetic, evolutional and cultural aspects related to the definition of human
skin color patterns.1,2

We believe that variations in skin color are evolutional
and are related to the regulation of the penetration of ultraviolet radiation (UVR).
3,4

The synthesis of vitamin D on the skin, degradation
of folic acid by UVR, resistance to direct sun exposure and cultural elements are
arguments that try to explain the phenotypical distribution of skin color in different
latitudes of the planet.5,6

Normal human skin color is mainly influenced by
the production of melanin, a dense high-molecular-weight brown pigment, that looks
darker the more concentrated it is.7-9

However, exogenous yellow pigments, the carotenoids,
also contribute to skin color, as well as endogenous red, oxygenated hemoglobin in
capillary vessels in the dermis, and endogenous blue, reduced hemoglobin in venulas.
7,9

In humans, skin and hair pigmentation depends on
the melanogenic activity inside melanocytes, melanin synthesis rate, as well as on
the size, number, composition and distribution of cytoplasm particles of the melanocytes
called melanosomes, in addition to the chemical nature of the melanin they have.8-11

Melanocytes and melanosomes have a relatively constant
number in different races, as discussed ahead.9

Melanocytes

Melanocytes are phenotypically important cells,
responsible for skin and hair pigmentation, contributing skin tone and providing
direct protection against the damages caused by UVR.9

They are dendritic cells, embryologically derived
from melanoblasts, which originate from the neural crest, migrating to the skin shortly
after the closing of the neural tube. This migration may occur to many destinations,
and the signalizer that direct this process still need to be better described.8,12

When they become fully developed cells, they spread
through different sites: the eyes (retina pigment epithelium, iris and choroid),
ears (vascular strias), central nervous system (leptomeninges), hair matrix, mucosas,
and skin.8,12

On the skin, they are located on the basal layer
of the epidermis and, occasionally, on the dermis. They project their dendrites
through the Malpighii stratum where they transfer their melanosomes to keratinocytes
(Figure 1). This melanocyte-keratinocyte association is
called epidermal melanin unit and is formed, in humans, by one melanocyte and
about thirty-six keratinocytes.8,13,14

Epidermal basal cells are united to adjacent
cells by specific structures called desmosomes and to the basement membrane
by hemidesmosomes. Melanocytes are not fixed on the epidermis; they can only
be identified by a small unevenness in their position in relation to the alignment
of the basal layer, projecting slightly towards the dermis (Figure
2).11

The density of melanocytes varies in different
parts of the body. There are about 2,000 or more epidermal melanocytes per square
millimeter of skin in the head and forearm, and about 1,000 in the rest of the
body, in all races. This exact regulation of the number of melanocytes on the
epidermis seems to be mediated by keratinocytes and by specific mediators like
the fibroblast growth factor (FGF2).11

The number of melanocytes goes down with age, in
areas not exposed to light, at the proportion of 6% to 8% per decade, and racial
differences in pigmentation are not due to a significant variation in the number
of melanocytes, but rather on their level of activity (melanosomes and melanin synthesis),
in the proportion of melanin subtypes (pheomelanin and eumelanin), their distribution,
and environmental factors like sun exposure, which directly stimulates the synthesis
of melanin.11,15

The melanin produced in melanocytes is stored in
specific intracytoplasmatic structures called melanosomes.

Melanosomes

Melanosomes are highly specialized elliptical
organelles, where there is synthesis and deposition of melanin (Figure
3), storage of the tyrosinase synthesized by ribosomes, and they are the
site of the biochemical phenomena that originate melanin.7

Melanin synthesis takes place exclusively in melanosomes
and dependents on many genes.

The fundamental phenotypical difference between
the more pigmented and less pigmented races does not reside on the production
of melanin, neither on the number of melanocytes, but mainly in the quality
of the melanosomes (Table 1)16.

Melanosomes are larger and more mature in black
people than in white people and are stored more as units than in clusters. The degradation
of larger melanosomes in keratinocytes is delayed, which also contributes to the
higher levels of skin pigmentation in these cases.8 The processes that
lead to this behavior difference need to be further clarified.

In normal skin melanosomes, melanin is extremely
dense. It is an insoluble high-molecular-weight nitrogenated polymer that forms a
pigment, which, in addition to providing color to the skin, plays a protection role,
filtering and absorbing UVR. It plays, therefore, an important photoprotective role
against UVR damages, as shown by the inverse correlation between the content of melanin
on human skin and the incidence of skin carcinomas and melanomas.11,17

Melanin

Melanin is the main biological pigment involved
in skin pigmentation, and is determinant for the differences in skin color.11

The initial element of melanin biosynthesis is tyrosine,
an essential amino acid. Tyrosine suffers the chemical action of tyrosinase, a copper
protein enzyme complex synthesized in the ribosomes and transferred through the endoplasmic
reticulum to the Golgi apparatus, and it is clustered in units surrounded by a membrane,
i.e. the melanosomes.11

The three members of the tyrosinase-related family
(tyrosinase, Tyrp 1 or tyrosinase-related protein 1, and Dct or dopachrome tautomerase)
are involved in the melanogenesis process leading to the production of either eumelanin
(brown-black) or pheomelanin (yellow-red).18

In the presence of molecular oxygen, tyrosinase
oxidizes tyrosine into dopa (dihydroxyphenylalanine) and this into dopaquinone. From
then on, the presence or absence of cysteine determines the course of the reaction
for the synthesis of eumelanin or pheomelanin.19

In the absence of cysteine (glutatione), dopaquinone
is converted into cyclodopa (leukodopachrom) and this into dopachrome. There are
two degradation pathways for dopachrome, one that forms DHI (dopa,5,6 dihydroxyindole)
at a larger proportion and another that forms a smaller quantity of DHICA (5,6 dihydroxyindole-2-carboxylic
acid). This process is catalyzed by dopachrome tautomerase (Tyrp 2-Dct). Finally,
these dihydroxyindoles are oxidized into melanin.19

Tyrosinase related protein 1 (Tyrp 1) seems to
be involved in the catalysis of the oxidation of DHICA into eumelanin. On the
other hand, in the presence of cysteine, dopaquinone rapidly reacts with this
substance to generate 5-S-cysteinyldopa and a smaller proportion of 2-S-cysteinyldopa.
Cysteinyldopas are then oxidized into benzothiazine intermediates and finally
produce pheomelanin (Figure 5).19

Eumelanin is an insoluble brown alkaline polymer,
and pheomelanin is a soluble yellowish alkaline pigment. Pigments similar to pheomelanin,
however, can be structurally derived from eumelanin, as it can be oxidized in the
presence of metallic ions, resulting in a lighter soluble pigment. Another sulfur-containing
pigment, derived from pheomelanin, which can be found in small quantities in red
human hair, and is called trichrome.13

In this manner, melanogenesis has three different
and important steps. The first step is the production of cysteinyldopa, which continues
as intense as the quantity of cysteine present. The second step is the oxidation
of cysteinyldopa to form pheomelanin, a process that depends on the quantity of cysteinyldopa
present. And the third and last step is the production of eumelanin, which only starts
after the depletion of most of the cysteinyldopa. However, eumelanin seems to deposit
on pre-formed pheomelanin and the ratio between pheomelanin and eumelanin is determined
by the activity of tyrosinase and availability of cysteine.19

Eumelanin absorbs and disperses ultraviolet light,
attenuating its penetration on the skin and reducing the harmful effects of the sun.
In other words, people with more pigmentation tend to get less sun burnt and to
tan more than those who are lighter skinned.15,20,21

Pheomelanin, on the other hand, has a great potential
to generate free radicals in response to UVR, which are capable of causing damage
to DNA, and, in this manner, may contribute to the phototoxic effects of UVR. This
explains why people with light skin, who have relatively high quantities of pheomelanin,
are at greater risk of ultraviolet-induced epidermal damage, including neoplasms.
20

Individual melanocytes typically synthesize eumelanins
and pheomelanins, and their rate is determined by a balance of variables, including
the expression of pigment enzymes and the availability of tyrosinase and specific
reducing agents in the cell.9

Melanocortin 1 receptor (MC1-R) controls the amount
of eumelanin and pheomelanin inside melanosomes. This proportion is an important
determinant of sun sensitivity in humans. However, probably the total quantity of
melanin produced is even more important than the ratio of the types of melanin.5
It is known that melanocytes derived from intensely pigmented skin present greater
quantity of total melanin and also a greater rate of eumelanin than the melanocytes
derived from light skins.10

Total skin melanin is the result of a combination
of monomers of pheomelanin and eumelanin and the proportion between the two determines
the final phenotypical expression of skin and hair color.

A reduction in eumelanin and the predominant presence
of pheomelanin, as in red-haired people, are regaled chiefly by MC1-R.11

Two types of melanin pigmentation are the basis
for normal skin color. Constitutive skin color is the genetically determined color
of healthy skin not exposed to UVR and it plays a key role in photoprotection against
the UVR that reaches the Earth, thus minimizing the damages to DNA that may lead
to the emergence of skin cancer.7,17

Facultative skin color is the more intense skin
color resulting from sun exposure or pigmentary diseases and reflects the genetically
determined tanning capacity in response to UVR. In this manner, the "tanning" level
is genetically determined and is the basis for the division of normal skin in adaptive
response patterns called phototypes.7

After the complete synthesis of melanin, melanosomes
filled with this pigment are injected in the interior of keratinocytes in the corresponding
epidermal melanin unit through the dendritic extensions of melanocytes (cytocin activity).
Once inside keratinocytes, melanosomes tend to spread through the cytoplasm, over
the upper part of the nucleus, so as to protect it from ultraviolet radiations. It
has been suggested that the pigment inside these cells also works as a scanner of
photoproduced free radicals, always striving to protect cell DNA.12,22,23

The photoprotection properties of the melanin of
human skin have been well documented and take place through the absorption and dispersion
both of ultraviolet light and visible light. This absorption increases linearly at
the range of 720-620 nm and then exponentially through shorter waves (300-600 nm).
17

Melanin has great affinity for DNA, and is capable
of producing reactive oxygen species in response to ultraviolet radiation A. In people
with light skin, the greater incidence of melanomas seems to result not only from
poor natural protection, but also from increased mutations promoting the formation
of pheomelanin and/or melanin intermediates.8,11,24

Ultra-structural studies revealed that eumelanosomes,
which are usually produced by dark skins, remain intact on the epidermis after exposure
to UVR, whereas in light skin, no intact melanosome can be detected after this radiation.
17

The main factors that regulate the quantity and
quality of the melanin produced by melanocytes include UVR, -MSH ( -type melanocyte
stimulating hormone or melanocortin), ASP (AGOUTI signaling protein), and MC1-R.8,25

Injections of α-MSH and β-MSH in human
individuals produced a darkening of the skin resulting from the high melanogenesis
inside epidermal melanocytes and increased transportation of melanosomes derived
from melanocytes, to keratinocytes, without the need of exposure to UVR. Hyperpigmentation
of the skin is also seen when human individuals were injected with high doses of
adrenocorticotropic hormone (ACTH).11,26,28,29

α-MSH is a tridecapeptide with a sequence
identical to the first 13 amino acids of ACTH. The proteolytic cleavage of proopiomelanocortin
(POMC), on the pituitary gland, is responsible for the origin of many byproducts,
including α-MSH. It is also known that POMC is expressed and suffers cleavage
in other places, including the brain and skin. α-MSH was the first of the peptides
derived from POMC to be identified on the skin.20

Human keratinocytes are capable of synthesizing
α-MSH and β-MSH at physiological quantities. α-MSH is also produced
in melanocytes and Langerhans cells.9,11,17,25,30-34 Evidences indicate
that these hormones play a paracrine role in the regulation of the functions of melanocytes.
More than 120 genes have been identified and seem to regulate pigmentation; however,
the effects of -MSH are mediated by MC1-R, which is expressed on the surface of melanocytes,
and is considered the key point for pigmentation. It is also present in other cells
like monocytes, neutrophiles, glioma cells, astrocytes, macrophages, fibroblasts,
endothelial cells, and keratinocytes. As MC1-R has a wide tissue distribution, it
probably is associated to a large number of biological functions.9,11,17,25,30,32-35

In 1992, Mountjoy et al.36 from the Oregon
University of Health Sciences, in Portland, reported they had cloned an MC1-R hormone
receptor, in humans and rats. They also demonstrated that mutations in the gene of
this receptor caused hair color changes in rats. In 1995, Valverde et al.37
reported a similar association between abnormal forms of the receptor and variations
in the skin and hair color of people.

In spite of the identification of more than 100
loci involved in the pigmentation of vertebrates, MC1-R is the chief determinant
of the pigmentation phenotype. The extension of its locus was first identified in
rats based on hair color changes. Recessive mutants had yellowish or pheomelanotic
hair, while wild-type rats had dark/brown or eumelanotic hair.9

In the early 90's, molecular structure of the MSH
receptor was described; it was then called MC1-R and its antagonist, AGOUTI signaling
protein (ASP). For many years, two loci were known to be involved in the qualitative
regulation (eumelanin and pheomelanin) and quantitative regulation of the pigmentation
of mammals, and ASP was produced in the follicles and acting in follicular melanocytes
through the inhibition of the synthesis of eumelanin.17,38,39 Before cloning,
two melanocortin receptors, MSH and ACTH receptors, were discovered in classical
pharmacological and physiological studies.

The melanocortin system consists of peptides with
many forms of MSH (alpha, beta and gamma) and ACTH; a family with five melanocortin
receptors, linked to protein G was described, with seven transmembrane domains (seven
passages through the membrane) and ASP.17,38,39

MC1-R was the first ?-MSH receptor that was cloned
and was isolated from a melanoma cell strain.34 Human MC1-R gene is located
in chromosome 16q24.3 and has a reading frame of 951 base pairs that codify a protein
with 317 amino acids. The human protein sequence shows all the characteristics of
the receptors coupled to protein G, including the presence of seven transmembrane
fragments and two sites of potential N-glicosilation. The occurrence of specific
high-affinity binding sites in most of the human melanocytes was already known, even
before the MC1-R gene was cloned.25,40,41 However, the number of binding
sites is variable, and it can be as low as a few hundreds per cell, as detected by
Scatchard's analysis using radiomarked probes. Not just α-MSH, but also ACTH,
β and γ MSH34 bind to MC1-R.

It is then a highly polymorphic white gene population
and these gene variations are associated with light skin and reddish hair and act
in the reduction of the ability of the epidermis to respond to UVR.

Today, the MC1-R gene is considered one of the main
markers of susceptibility to malignant skin neoplasms, as gene variants are associated
to an increased risk of melanoma and non-melanoma skin cancers.17,30,34,42-44

Other studies demonstrated that solar ephelis and
lentigines are different types of pigmented lesions that present significant differences
in their etiologies, but gene variants of MC1-R are a necessary factor for the development
of ephelis, while they play a less important role in the case of lentigines.3,30,45,46

Variations related to gene MC1-R are exceptionally
high among Caucasians and have a significant impact on the pigment phenotype of this
ethnic group. Red hair has been related to some alleles, but recent studies indicate
that the same genotypes may express different hair colors depending on the population.
3,44

MC1-R is abundantly expressed in human and rat melanoma
cells, and at significantly lower levels in rat melanocytes. More recently, it has
been demonstrated in normal glands of human skin and hair follicles, as well as in
skin malformations and neoplasms.34

In most individuals with light skin, who do not
tan, there is a variation in the gene sequence of classical MC1-R, which normally
determines dark hair and ease to tan.11 In individuals with reddish hair
and light skin that have a predominance of pheomelanin in the hair and skin and/or
reduced ability to synthesize eumelanin, a functional reduction of MC1-R with a resulting
decrease in the melanotropin-induced tyrosinase activity, associated with eumelanogenesis,
can be the key in the promotion of pheomelanin synthesis inside human melanocytes.

In this manner, the MC-1R of melanocytes is undoubtedly
an important element in the regulation of pigmentation in mammals, but also one of
the most polymorphic.11,20,30,32-34,47 Variant gene sequences are found
in more than 80% of people with red hair and light skin, in less than 20% of individuals
with brown or black hair and in less than 4% of those who respond easily to tanning.
34

α-MSH signals through MC1-R, activating
adenyl cyclase (AC) and increasing intracellular cyclic adenosin monophosphate
(AMPc), resulting in the production of dark eumelanin pigment (Figure
6). Whether MC1-R is involved in other signaling pathways, still remains
unknown, but the activation of MC1-R influences the relative quantities of pheomelanin
and eumelanin produced, and its activity loss is associated to red or yellow
hair.20,34,38,39,48-52

Variants of MC1-R have been associated with red
hair inheritance, in which more yellow-reddish pheomelanin pigment is produced and
they present very small tanning capacity. MC1-R variants R160W, R151C, D294H, R142H,
86insA, and 537insC are the main determinants of the red hair and light skin phenotype.
It is a phenotype typical of phototypes I and II, with greater chance of sun burn
and development of skin neoplasms.10,20,34

The recently cloned murine gene AGOUTI is located
in chromosome 2 and codes protein ASP formed by 131 amino acids and acts as a competitive
antagonist of MC1-R, blocking its activation by α-MSH. However, the shift between
eumelanogenesis and pheomelanogenesis involves the opposition to ASP and α-MSH
effects as binders for MC1-R. Pheomelanogenesis can be stimulated by in vitro
treatment with purified recombinant ASP. After treatment with ASP, the expression
of genes that codify tyrosinase and other melanogenetic proteins is suppressed in
melanocytes, which requires other physiological factors typical of in vivo
pheomelanogenesis. In normal human melanocytes, where the number of expressed MC1-R
is relatively low, ASP completely annuls α-MSH stimulating effects in melanocytic
and melanogenesis proliferation.17,25,53

The incapacity to tan of individuals with variation
in MC1-R is consistent with the critical role MSH/AMPc play in this response, but
some studies indicate that damages to melanocyte DNA may mediate pigmentation induced
by UVR.54

UVR and Pigmentation

The solar radiation spectrum is broad, ranging from
cosmic rays (ultra X rays) to infrared radiation. Shorter wavelength radiations,
up to 200 nm, do not reach the Earth, because they are absorbed by atmospheric oxygen
and ozone.17,55 UVR and visible light are between 200 nm and 760 nm and
form the photobiological spectrum, with ultraviolet between 200 and 400 nm and visible
light between 400 and 760 nm. Beyond this limit, up to 17000 nm is infrared, which
is a heat inducer.17,55

The acute effects of exposure to UVR are basically
two: skin burn and/or tanning. The individual response to exposure to UVR, that is,
how tanned one may get, is one of the best examples of human adaptation to the environment.
9

After one single exposure to UVR, an increase in
the size of melanocytes can be observed, followed by an increase in tyrosinase activity.
Repeated exposures to UVR lead to an increase in the number of stage IV melanosomes
transferred to keratinocytes, as well as an increase in the number of active melanocytes.
Moreover, the density of melanocytes, in comparative studies, is greater in photoexposed
areas.16

Therefore, UVR is an efficient stimulant of skin
pigmentation in humans and is responsible for the initiation of the tanning response.
Many mechanisms may be involved and the response is believed to be the result of
a combination of different signals acting both directly and indirectly in melanocytes.
Indirect UVR action involves the release of keratinocyte mediators in the skin.33,40

Ultraviolet-B radiation (UVB) on human skin induces
the production of α-MSH and ACTH in melanocytes and keratinocytes. α-MSH
stimulates the activity of tyrosinase and in vivo melanin synthesis, and the
synthesis of melanocytes through MC1-R. Other reports indicate that the irradiation
of melanocytes with UVR increases MC1-R RNAm levels. Moreover, the synthesis of many
epidermal factors, including α-MSH, ACTH and endothelin-1, is increased by
the exposure to UVR, suggesting an important influence of these mediators on the
response of melanocytes to sun light.32,56-58

UVB is the chief cause of sun burn, causing erythema
after a latency period of 2 to 7 hours. UVA causes erythema that appears later and
may gradually become more intense.55

The interaction of hormones and UVR can be illustrated
in melasma. UVR stimulates the production of melanocortin inside melanocytes and
keratinocytes, which explains the involvement of this hormone in the pathogenesis
of melasma that is basically characterized by increased epidermal melanization in
melanocytic proliferation.11

Melasma

Melasma is a common, acquired and symmetrical
hypermelanosis characterized by more or less dark brownish maculae, with irregular
contour, but clear limits, on photoexposed areas, especially the face, forehead,
temples, and more rarely on the nose, eyelids, chin, and upper limbs (Figure
7).59-62

It is a dermatological disease easily diagnosed
by clinical examination, typically chronic, with frequent recurrences, great refractoriness
to existing treatments, and with many unknown physiopathological aspects.57

The word melasma comes from the Greek melas
that means black. Chloasma is a term used with the same meaning, also derived from
the Greek cloazein, meaning greenish. The word melasma is, therefore, the
most appropriate designation for the condition.59

Although it may affect both sexes and all races,
it is more often in intermediate phototypes and people of Asian or Hispanic origin
that live in tropical areas. It is more common in adult women in childbearing age,
but its onset can also be after menopause. The age of onset is usually between 30-55
years and men account for only 10% of cases.7,57,61,63,64

Even though melasma is more frequent among Hispanics,
its exact prevalence is unknown. Approximately 66% of Mexican women develop melasma
during pregnancy and one third of these women keep the pigmentation for the rest
of their lives.65-67

To provide an idea of this disease, according to
a 2000 census in the United States, Hispanics accounted for 12.6% of the population
and this number is estimated to grow annually to 15.5% in 2010 and 24.4% in 2050.
65,67

There is no consensus as to the clinical classification
of melasma. Two patterns of facial melasma are recognized: central-facial, which
affects the central region of the forehead, mouth, lips, supra labial area, and chin;
and malar, which affects the zygomatic region. Some authors also add a third and
less frequent pattern, called mandibular. Ponzio & Cruz observed in a study, that
78.7% of the melasmas were central and 21.3% were peripheral.59,63,68

There are countless factors involved in the etiology
of the disease, but none of them can be mentioned as the only factor leading to its
development. They include: genetic influences, exposure to UVR, pregnancy, hormone
therapy, cosmetics, phototoxic drugs, endocrinopathies, emotional factors, anti-convulsive
drugs, and others with historic value. However, it seems that genetic predisposition
and exposure to sun radiation play an important role, considering that melasma lesions
are more evident during or shortly after periods of exposure to the sun.7,60,62,63,68-70

Sacre et al., investigating idiopathic melasma,
concluded that thyrotropin, prolactin, and gonadotrophin reserves are normal and
that, as ovary and thyroid functions were also normal, it was not possible to establish
a correlation between hormone levels and this form of melasma.71

In contrast with what happens in pregnancy, melasma
induced by anovulatory drugs does not regress with the suspension of the drug and,
among the patients that had melasma because of birth control pills, 87% had also
had it in previous pregnancies.63

Genetic predisposition has been suggested by reports
of family occurrence. A racial factor has been reported due to the frequent occurrence
of melasma Hispanic patients. Sanchez et al. Identified family history in more than
20% of the cases studied, and all patients reported exacerbation due to sun light
and the use of cosmetics.59,72

It is worth highlighting that melasma is one of
the unaesthetic dermatoses that lead to great demand for specialized dermatological
care, even though they are just a common and benign pigmentation abnormality. This
might be explained by its cosmetically compromising nature and the associated emotional
and psychological effects in individuals affected by this problem, who often, because
of dissatisfaction with their appearance, eventually reduce their social lives, even
with cases of suicide reported.65-67,69

Although this condition often has only aesthetical
implications, such concern can be very important and impacting on the social, family
and professional lives those affected, causing psychological effects that cannot
be neglected.65,73

In 2003, Melasqol, a new tool for assessing health-related
quality of life in women with melasma, was published by Balkrishnan et al..
This instrument was validated and demonstrated utility to monitor the impact caused
by melasma on the quality of life of patients. The main quality of life domains that
showed to be affected by melasma were social life, recreation, leisure, and emotional
well being. In 2006, this tool was translated into Portuguese and culturally adapted,
according to the rules defined by the World Health Organization.65-67,74

The treatment of melasma is usually dissatisfactory
due to the great recurrence of lesions and due to the absence of a definitive whitening
alternative. Controlled clinical trials indicate photoprotection and the use of whiteners
as the first line elements of its treatment.75-77 However, the discussion
about the many treatment modalities, in spite of the great clinical and academic
interest, is outside the scope of this paper.

This being the case, contributing to the understanding
of the mechanism through which melanocytes promote localized phenotypical coloration
or how skin color is genetically pre-determined and changes color induced by factors
like sun light, hormones, inflammations, and others, is a task of major importance,
and such clarifications may provide relevant support to treatment innovations and,
consequently, improve the quality of life of patients.

Jointly, comparative studies on skin affected by
melasma and normal adjacent skin found that this condition is characterized by epidermal
hyperpigmentation without increase in the number of melanocytes, increase in the
quantity of melanin in all layers of the epidermis, increase in the number of melanosomes,
and augmented dermal elastosis.57,78 Dermal pigmentation does not differ
on the epidermis with melasma and on healthy adjacent skin, this finding goes against
the classification of melasmas in epidermal, dermal and combined, as proposed by
Wood.2,57,59,63

Recent studies indicate that countless peptides
play an autocrine or parocrine regulation in human skin melanocytes and in many pigmentary
diseases. They are represented mainly by: endothelin 1 (ET-1), granulocyte macrophage
colony-stimulating factor, and membrane-bound stem cell factor (SCF). Growth related
oncogene- is also known to regulate the interactions between melanocytes and keratinocytes,
hepatocyte growth factor, and soluble stem cell factor for interactions between fibroblasts
and melanocytes.1,79,80

This inter-relation also involves some specific
receptors expressed in melanocytes, like endothelin-B receptor, stem cell factor
receptor, and c-KIT. Up or downregulation of this interconnected network is intrinsically
involved in the stimulation melanocytic functions in many epidermal disorders that
evolve with pigmentation alterations.79,80

Immunohistochemical findings suggest that a strong
immunoreactivity to α-MSH on skin with melasma is one of the leading factors
in the genesis of this disease. The relationship between the photoexposed area and
enhanced immunoreactivity to α-MSH on affected skin has not yet been clarified.
However, the existence of a yet unknown signaling pathway, with increased expression
of MC1-R, which may play a significant role in this greater immunoreactivity to α-MSH
should be investigated. There are evidences that a strong expression of α-MSH
antigen in the keratinocytes of the skin affected with melasma, suggesting that α-MSH
plays a key role in the hyperpigmentation of skin with melasma.57,81

In this manner, the evaluation of the expression
of α-MSH and MC1-R in the epidermis with melasma lesions, compared to healthy
perilesional skin, would permit estimating the role of MC1-R pathway in the physiopathogenesis
of the disease.

Moreover, β-estradiol increases the expression
of α-MSH and MC1-R in melanocytes.51 In addition to that, a recent
study demonstrated an increased expression of estrogen receptors on skin with melasma,
as compared to normal skin, but only two patients were qualitatively evaluated, which
does yet not permit determining the real function of this receptor and of estrogen
in the physiopathogenesis of melasma.82

FINAL CONSIDERATIONS

Melasma is a frequent disease in the general population
that causes great impact in the quality of life of patients and drives great efforts
to clinical and pharmaceutical research for the development of treatments. However,
the knowledge of its physiopathogenesis is still very limited.65,83

The investigation of estrogen receptors on the epidermis
and in melanocytes of healthy and affected skins would enlighten the role sexual
steroid hormones play in the process of localized hyperpigmentation of this disease.
84-88

Research on allele variants of MC1-R that express
differently in healthy and affected skin could explain the more effective pigmentation
in certain photoexposed areas than in others.30,46,89

The culture of keratinocytes and melanocytes from
healthy and melasma skin and of populations not affected by the disease, under different
exposures, would permit a comparative study of the expression of many genes to demonstrate
the bases of the different phenotypical behavior of these groups of adjacent cells
on the same tissue.90,91

Clinical experimentation with AGOUTI proteins in
melasma lesions that compete with α-MSH in MC1-R receptors, could provide physiopathological
grounds for the understanding of the role of -MSH/MC1-R system in the physiopathogenesis
of the disease.79,92

Profiles of melanogenetic cytokines expressed in
healthy and affected skins, as well as their cells of origin, local consequences,
and triggering stimulus would provide the understanding of the elements involved
in the genesis of melasma.79,80,93,94

Finally, population-based epidemiological studies
or with subgroups of patients with melasma, like pregnant women, post-menopausal
women or men would also contribute to the design of new hypotheses for the natural
history and physiopathogenesis of melasma.